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Disruption of the NAD(P)H:quinone oxidoreductase 1 (NQO1) gene in mice causes myelogenous hyperplasia.
- Source :
-
Cancer research [Cancer Res] 2002 Jun 01; Vol. 62 (11), pp. 3030-6. - Publication Year :
- 2002
-
Abstract
- NAD(P)H:quinone oxidoreductase1 (NQO1) is a cytosolic protein that reduces and detoxifies quinones and their derivatives, thus protecting cells against redox cycling and oxidative stress. Disruption of the NQO1 gene in mice caused myeloid hyperplasia of bone marrow and highly significant increases in blood neutrophils, eosinophils, and basophils. NQO1-null mice also showed a decrease in lymphocytes and WBCs as compared with wild-type mice. Various techniques also demonstrated an increase in megakaryocytes without an increase in blood platelets. Histological analysis of liver, kidney, spleen, and thymus did not demonstrate a difference between wild-type and NQO1-null mice or a sign of infection. Blood cultures and urine analysis also did not demonstrate any sign of infection in NQO1-null and wild-type mice. Additional analysis of the bone marrow from NQO1-null mice revealed that loss of NQO1 alters the intracellular redox status because of accumulation of NAD(P)H, cofactors for NQO1. This causes a reduction in the levels of pyridine nucleotides and tumor suppressor proteins p53 and p73, and a decrease in apoptosis. The decrease in apoptosis causes myelogenous hyperplasia in NQO1-null mice. These results demonstrate that NQO1 acts as an endogenous factor in the protection against myelogenous hyperplasia. This is significant because 2-4% of human individuals without known abnormalities, and >25% of individuals with benzene poisoning and acute myelogenic leukemia are homozygous for a mutant allele (P187S) of NQO1 and lack NQO1 protein/activity.
- Subjects :
- Animals
Apoptosis genetics
Bone Marrow Cells enzymology
Bone Marrow Cells metabolism
Bone Marrow Cells pathology
Bone Marrow Cells ultrastructure
Cell Differentiation genetics
Chromosomes
DNA-Binding Proteins metabolism
Female
Genes, Tumor Suppressor
Hyperplasia enzymology
Hyperplasia genetics
Male
Mice
Myeloproliferative Disorders blood
Myeloproliferative Disorders enzymology
NAD(P)H Dehydrogenase (Quinone) metabolism
NADP metabolism
Nuclear Proteins metabolism
Tumor Protein p73
Tumor Suppressor Protein p53 metabolism
Tumor Suppressor Proteins
Myeloproliferative Disorders genetics
NAD(P)H Dehydrogenase (Quinone) genetics
Subjects
Details
- Language :
- English
- ISSN :
- 0008-5472
- Volume :
- 62
- Issue :
- 11
- Database :
- MEDLINE
- Journal :
- Cancer research
- Publication Type :
- Academic Journal
- Accession number :
- 12036909